The present invention relates to a method of inhibiting the binding of platelet-derived growth factor (PDGF) using N-alkyl- and N-aryl-sulfonyl phthalimides, maleimides and heterodicarboxamides.
The invention also relates to certain N-alkyl- and N-arylsulfonyl phthalimides, maleimides and heterodicarboxamides useful as inhibitors of PDGF.
Furthermore, the invention relates to a pharmaceutical composition comprising an N-alkyl- or N-aryl-sulfonyl phthalimide, maleimide or heterodicarboxamide useful as an inhibitor of PDGF.
The platelet-derived growth factors (PDGF) are a family of polypeptide mitogens, produced by a variety of different cell types, which stimulate the proliferation of most mesenchymal cells and possibly certain epithelial and endothelial cells. PDGF binds to specific cell surface receptors which possess intrinsic tyrosine kinase activity. Binding of PDGF activates the kinase activity, thereby initiating a cascade of biochemical events culminating in cell division. PDGF cell division can occur by a paracrine mechanism, in which PDGF produced by one cell stimulates the division of other cells, or by an autocrine mechanism, in which a cell stimulates its own division by endogenous production of PDGF.
A compound which inhibits the binding PDGF to its receptor blocks the biological activity of the growth factor. This biological activity includes vascular cell proliferation in atherosclerosis or restenosis following angioplasty or vascular surgery, and division of certain tumor cells, fibroblasts, mesangial cells and epidermal cells. PDGF is also a potent chemotactic agent, stimulating infiltration of macrophages into arterial tissue in atherosclerosis and into the glomerulus in glomerulonephritis. PDGF is also involved in the elaboration of extracellular matrix proteins by retinal pigment epithelial cells, indirectly leading to retinal detachment and blindness. Therefore, a PDGF inhibitor should be useful in the treatment of a variety of diseases, including atherosclerosis, cancer, retinal detachment, pulmonary fibrosis, arthritis, psoriasis and glomerulonephritis, and for blocking the smooth muscle cell hyperplasia which occurs in transplant atherosclerosis and following angioplasty or vascular surgery.